AlCl3and BDMAEE: A pair of potent reactive regulators of aryl grignard reagents and highly catalytic asymmetric arylation of aldehydes

Article abstract of DOI:10.1002/chem.201000974

Figure Presented Cheap, energy-saving, and applicable: With the aid of AlCl₃ and BDMAEE [2,2′-oxybis(N,N-dimethylethanamine)], a highly asymmetric catalytic addition of various aryl Grignard reagents to aldehydes was achieved under mild conditions with easily prepared (S)-H ₈-BINOL and inexpensive commercially available Ti(OiPr)₄ (see scheme), and the reaction could be easily scaled up with no loss of yield and enantioselectivity.

Full text of DOI:10.1002/chem.201000974

DOI: 10.1002/chem.201000974
AlCl3 and BDMAEE: A Pair of Potent Reactive Regulators of Aryl Grignard
Reagents and Highly Catalytic Asymmetric Arylation of Aldehydes
Xin-Yuan Fan,[a] Yong-Xin Yang,[a] Fang-Fang Zhuo,[a] Sheng-Li Yu,[a] Xiao Li,[a]
Qi-Peng Guo,[a] Zhi-Xue Du,[a] and Chao-Shan Da*[a, b]
Enantioenriched diarylmethanols are important constitu-
ents of many biologically active compounds. As a result, the
synthesis by the catalytic asymmetric arylation of aldehydes
has generated an enormous amount of attention.[1] The
seminal report by Fu and co-workers[2] on the asymmetric
addition of diphenylzinc to aldehydes was followed shortly
thereafter by the first highly enantioselective method by Pu
et al.[3] A more enantioselective method involves the addi-
Harada and co-workers,[11] who developed a highly enantio-
selective protocol based on Grignard reagents. A drawback
to their method was the need to add ArMgBr to titanium
tetraisoproxide at À788C and then to introduce the resulting
mixture into the reaction for two hours. Although very
useful on a laboratory scale, large-scale reactions at very
low temperatures are impractical. A significant operational
and economical improvement would be the advancement of
a method that could be conducted at room temperature, fa-
cilitating large-scale synthesis of highly enantioenriched di-
À
À
tion of mixed aryl Zn alkyl intermediates to aldehydes.
These intermediates can be prepared from diphenylzinc[4] or
arylboronic acids and diethylzinc[5] as described by Bolm
and others.[6] In pursuing an economical procedure, Walsh
and co-authors developed a cost-effective protocol starting
from inexpensive and readily available arylbromides to pre-
pare arylzinc reagents. N,N,Nꢀ,Nꢀ-Tetraethylethylene di-
ACHUTNGRENaNUG rACTHUNGRTENyUNG lmethanols. Herein we report a highly asymmetric cata-
lytic addition to aldehydes by using aryl Grignard reagents.
The Grignard reagents are converted into triarylaluminum
intermediates in situ, and are added to aldehydes with high
enantioselectivities. To the best of our knowledge, no such
report has been previously disclosed.
ACHTUNGTRENNUNGamine was used as a potent inhibitor of the Lewis acidic
LiCl, which was formed on the transmetallation of the aryl-
lithium to zinc chloride and rapidly promotes the undesired
background reaction.[7] Other successful works include salt-
free triarylaluminum as nucleophiles by Gau and co-work-
ers,[8] and Ru-catalyzed direct asymmetric arylation with ar-
ylboronic acids by Yamamoto, Miyaura, and co-workers.[9]
In comparison to other aryl sources, aryl Grignard re-
agents are one of the least expensive and most commonly
employed organometallic reagents. They are rarely used in
the catalytic addition to aldehydes because of their high re-
activity.[10] So far only one case has been disclosed by
We pursued the development of a practical, room-temper-
ature method starting from our recent research on the cata-
lytic asymmetric addition of deactivated alkyl Grignard re-
agents to aldehydes outlined in Scheme 1.[12] In this reaction,
MgBr2 and MgBrACHTUNTRGNEUNG(OiPr) are formed. These Lewis acids pro-
mote the background reaction to form the racemic product
and lower the enantioselectivity of the process. 2,2ꢀ-Oxy-
bis(N,N-dimethylethanamine) (BDMAEE) was used as an
additive to chelate the in situ generated Lewis acids MgBr2
and MgBrACTHNUTRGENUG(N OiPr) and to suppress their activity so that the
asymmetric catalytic additions are highly enantioselective.
However, PhMgBr becomes quite unreactive after coordina-
tion of BDMAEE. This result suggested that the chelation
significantly decreased the nucleophilicity of PhMgBr.
Owing to the inability of the aryl Grignard reagents to
[a] X.-Y. Fan, Y.-X. Yang, F.-F. Zhuo, S.-L. Yu, X. Li, Q.-P. Guo,
Z.-X. Du, Prof. Dr. C.-S. Da
Institute of Biochemistry & Molecular Biology
School of Life Sciences, Lanzhou University
Lanzhou 730000 (China)
transfer aryls to TiACHTNUGTRNEUNG(OiPr)4 in the presence of BDMAEE, we
Fax : (+86)931-8915208
E-mail: dachaoshan@lzu.edu.cn
[b] Prof. Dr. C.-S. Da
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000974.
Scheme 1.
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Chem. Eur. J. 2010, 16, 7988 – 7991

COMMUNICATION
decided to search for a more electrophilic metal that would
be able to accept an aryl group from the deactivated
Grignard reagent and arylate the aldehyde. After screening
a variety of possibilities, we identified AlCl3. As mentioned
earlier, Gau demonstrated that salt-free aryl aluminum re-
agents could be added to aldehydes with high enantioselec-
tivity. One drawback of Gauꢀs method is that it is difficult to
obtain salt-free aryl aluminum reagents.[8]
To examine the possibility of employing aluminum re-
agents in the asymmetric arylation of aldehydes, 2-chloro-
benzaldehyde was used in the presence of (S)-BINOL and
titanium tetraisoproxide. As shown in Table 1 (entries 1–2),
hyde, as outlined in Scheme 2. The BDMAEE is believed to
sequester the magnesium salts to prevent them from pro-
moting the racemic background reaction. Note that AlPh3
has only one open coordination site and [(BINOLate)Ti-
ACHUTNRGEN(NUG OiPr)2] and TiCAHTUNGTRNE(NUGN OiPr)4 have two. In contrast, the magnesium
probably binds the BDMAEE in a tridentate fashion, as
shown in Scheme 1. As suggested by the groups of Bolm[5]
and Walsh with diamines and lithium,[7] and subsequently by
us,[12] BDMAEE chelates the Lewis acids MgX2 and thus
strongly suppresses the undesired reaction catalyzed by
MgX2, which can lead to a poor enantioselectivity. Then
À
AlPh3 transfers phenyl to TiACTHNUGTRENUNG(OiPr)4 to generate Ph Ti-
AHCTUNGTERG(NUNN OiPr)3, which is supposed to subsequently form a bimetallic
nuclear complex with the (S)-BINOL-TiACTHNUTRGENUG(N OiPr)2 and alde-
Table 1. Catalytic asymmetric addition of PhMgBr to 2-ClC6H4CHO.[a]
Entry PhMgBr [mmol] BDMAEE [mmol] AlCl3 [mmol] ratio[b]
hyde.[13]
ee [%][c]
As mentioned earlier, to develop a truly practical method
for the arylation of aldehydes, we examined catalytic asym-
metric arylation reactions at room temperature. For high
enantioselectivity, however, most catalytic asymmetric reac-
tions must be carried out at low temperature, which can be
difficult to accomplish on a large scale. In a study of the
affect of temperature on product ee, we found that our
system gave the highest enantioselectivities at room temper-
ature, in which complete conversion to the diaryl methanol
was observed in three hours. Interestingly, lower tempera-
tures resulted in decreased enantioselectivity and longer re-
action times (Table 2, entries 1–3). With all these efforts,
however, the highest enantioselectivity was only 77%. Con-
sidering the reports that optically active H8-BINOL was
1
2
3
4
5
6
7
8
9
0.81
0.81
0.75
0.81
0.90
0.81
0.81
0.81
0.81
1.08
1.08
0.81
0
0.75
0.81
0.90
0.3
0.9
1.05
1.2
0
2.7:2.7:0
2.7:0:1
5
38
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.4
0.4
2.5:2.5:1 50
2.7:2.7:1 54
3.0:3.0:1 50
2.7:1.0:1 52
2.7:3.0:1 65
2.7:3.5:1 73
2.7:4.0:1 69
2.7:3.5:1 77
2.7:3.5:1 76[d]
10
11
1.4
1.4
[a] Ratio of (PhMgBr/BDMAEE/AlCl3)/TiACHTUNRTGNEUNG(OiPr)4/(S)-BINOL-Ti/aldehyde=
0.3:0.3:0.025:0.25 mmol unless otherwise noted. [b] Ratio of PhMgBr/
BDMAEE/AlCl3. [c] Determined by HPLC. [d] First introduction of BDMAEE
and then AlCl3 to PhMgBr.
in the absence of AlCl3 or
BDMAEE, very low enantiose-
lectivity was observed (<40%).
Furthermore, in the absence of
AlCl3, the reaction was very
slow. In contrast, when the in-
hibitor BDMAEE and AlCl3
were used together, the enan-
tioselectivity was higher and
Scheme 2. The proposed reaction mechanism.
the reaction reached comple-
tion very quickly (Table 1,
entry 4). The ratio of AlCl3/
BDMAEE/PhMgBr was found to be critical for high enan-
tioselectivity and yield. It was found that 2.7 equivalents of
PhMgBr to AlCl3 resulted in the higher enantioselectivity
(Table 1, entries 3–5). The enantioselectivity again climbed
when the equivalents of BDMAEE was increased (Table 1,
entries 6–9), with the best ratio of PhMgBr/BDMAEE/
AlCl3 of 2.7:3.5:1 (Table 1, entry 8). An increase in the
amount of PhMgBr/BDMAEE/AlCl3 relative to aldehyde
led to a slight increase in the enantioselectivity (Table 1,
entry 10). The order of introduction of BDMAEE and
AlCl3 did not change the enantioselectivity (Table 1, en-
tries 10 and 11).
Table 2. The effect of temperature on the catalytic addition.[a]
Entry
Temperature [8C]
Time [h]
ee [%][b]
1
2
RT
0
3
8
79
71
58
94
3
À20
16
3
4[c]
RT
[a] Ratio of (PhMgBr/BDMAEE/AlCl3)/TiACTHNUTRGNENUG(OiPr)4/BINOL-Ti/aldehyde=
0.4:0.4:0.025:0.25 mmol. [b] Determined by HPLC. [c] (S)-H8-BINOL
was used instead of (S)-BINOL.
more enantioselective than BINOL in the asymmetric cata-
lytic reactions,[8,14] (S)-H8-BINOL was used instead of (S)-
BINOL. Fortunately, the enantioselectivity increased to
94% (Table 2, entry 4).
We propose that the role of AlCl3 is to accept the Ph
group from the Grignard reagent to generate the intermedi-
ate AlPh3, which ultimately transfers the aryl to the alde-
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C.-S. Da et al.
Under the optimal conditions in Table 2, entry 4, a series
of aldehydes with PhMgBr were screened (Table 3, en-
tries 1–15). Note that the in situ generated AlPh3 intermedi-
ferent aryl Grignard reagents were screened and all of them
achieved high yields and enantioselectivities. We initially
employed (2-naphthyl)MgBr and afforded 95–98% enantio-
selectivities (Table 3, entries 16–17). The meta-substituted
aryls addition to aldehydes has been rarely reported previ-
ously. We used (3-tolyl)MgBr and (3-MeO)C6H4MgBr and
both of them also provided ꢀ90% enantioselectivities
(Table 3, entries 18–20). Three different ArMgBr reagents,
with electron-donating or electron-withdrawing para-sub-
stituents (Table 3, entries 18–26), all gave excellent enantio-
selectivities and yields, and particularly, the highest enantio-
selectivity was up to 99%. In addition, the heteroatom-con-
taining (benzofuran-5-yl)MgBr achieved a high ee and yield
(Table 3, entry 27).
Because of the simple and convenient operation and mild
conditions, the reaction was successfully scaled up to 2.0 g
with no loss of enantioselectivity or yield, indicating this
process has great potential for industrial applications
(Scheme 3). To the best of our knowledge, this is the first
catalytic asymmetric arylation of an aldehyde with aryl
Grignard reagents on a large scale.
Table 3. Catalytic asymmetric ArMgBr addition to aldehydes.[a]
Entry
Ar
R
Yield [%][b]
ee [%][c,d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-ClC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
94
94
92
95
93
95
97
94
95
90
95
96
94
91
91
92
90
93
90
92
96
94
96
93
92
95
83
94 (92) [90]
97
96 (95) [94]
95
97 (96) [95]
95 (97)
96 (94)
97 (95) [90]
98 (96)
86 (91)
99 (96) [95]
95 (94) [91]
96 [90]
95 [80]
94
95
98
95
92
90
96
99
98
95
95
3-(MeO)C6H4
4-(MeO)C6H4
3-MeC6H4
4-MeC6H4
4-(CF3)C6H4
(E)-PhCH=CH
1-naphthyl
2-naphthyl
2-thienyl
c-hex[e]
CH3ACHTUNGRETNNU(G CH2)8
2-naphthyl
2-naphthyl
3-tolyl
3-(MeO)C6H4
3-(MeO)C6H4
4-tolyl
4-FC6H4
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
benzofuran-5-yl
1-naphthyl
c-hex[e]
1-naphthyl
C6H5
4-MeC6H4
1-naphthyl
1-naphthyl
2-naphthyl
C6H5
1-naphthyl
2-thienyl
1-naphthyl
Scheme 3.
97
87
In summary, we have successfully developed a truly prac-
tical catalytic asymmetric arylation of aldehydes by using a
variety of aryl and heteroaryl Grignard reagents with enan-
tioselectivities as high as 99%. The key is the use of a com-
bination of AlCl3 and BDMAEE, which play distinct roles
in the reaction system. BDMAEE inhibits the undesired
background reaction promoted by Lewis acidic MgX2,
whereas AlCl3 serves as an in situ generated aryl intermedi-
ate capable of transfer of the aryl to titanium and then to al-
dehydes under mild conditions. Note that use of in situ gen-
erated AlAr3 reagents circumvents the need to isolate salt-
free aryl aluminum reagents, greatly simplifying the asym-
metric arylation process. In most cases, the in situ generated
aryl intermediates resulted in slightly higher enantioselectiv-
ities than the salt-free Ar3Al protocol and the intermediate
[a] Ratio of (PhMgBr/BDMAEE/AlCl3)/TiACTHNUTRGNEUNG(OiPr)4/(S)-H8-BINOL-Ti/al-
dehyde=0.4:0.4:0.025:0.25 mmol. [b] Isolated yield. [c] Determined by
HPLC. [d] The ee in the parentheses is referenced from Gauꢀs report,[8]
the ee in the square bracket is referenced from Haradaꢀs report.[11] [e] c-
Hex=cyclohexane.
ate achieved a slightly higher ee than that reported for salt-
free AlPh3,[8] except with substrates 4-(MeO)C6H4CHO and
(E)-cinnamaldehyde (Table 3, entries 1, 3, and 5–12). Our
procedure also resulted in slightly higher enantioselectivity
than Haradaꢀs procedure (Table 3, entries 1, 3, 5, 8, and 11–
13), especially with alkyl aldehydes (Table 3, entry 14).[11] As
can be seen in Table 3, in all cases with PhMgBr we ob-
tained ꢀ90% yields. The aromatic and heteroaromatic alde-
hydes with electron-donating and electron-withdrawing sub-
stituents were found to undergo arylation with PhMgBr
with excellent enantioselectivities (ꢀ94%; Table 3, en-
tries 1–9 and 11–13), in particular, up to 99% ee for 1-naph-
thylaldehyde (Table 3, entry 11). Most significantly, aliphatic
aldehydes, including the challenging class of linear aliphatic
aldehydes, provided benzylic alcohols with ꢀ94% ee
(Table 3, entries 14–15).
ArTiACHTNUGRTENNUG(OiPr)3 directly from ArMgBr with TiACHTUNTGERN(NUGN OiPr)4. Further-
more, the fact that the reaction can be conducted at room
temperature with inexpensive Grignard reagents facilitates
large-scale procedures necessary to produce pharmaceutical
intermediates. An additional benefit of this process is that it
employs H8-BINOL, which is commercially available or pre-
pared in one step from enantioenriched BINOL, one of the
least expensive chiral ligands in asymmetric catalysis. With
these attributes, and the well-recognized biological activity
of enantioenriched diarylmethanols, we are confident that
this reaction will find application in the pharmaceutical in-
dustry.
Having developed a method for phenyl additions to alde-
hydes, we wanted to explore the use of substituted and func-
tionalized aryl Grignard reagents. Thus, additional seven dif-
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Chem. Eur. J. 2010, 16, 7988 – 7991

Asymmetric Synthesis and Catalysis
COMMUNICATION
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Experimental Section
General procedure of catalytic asymmetric addition of aryl Grignard re-
agents to aldehydes: An argon-purged flask was charged with PhMgBr
(1.1 mL, 1.0 mmol) in THF (1.1 mL), and then AlCl3 (53 mg, 0.4 mmol)
in THF (0.4 mL) was added dropwise. After stirring for 12 h at room
temperature, BDMAEE (263 mL, 1.4 mmol) was added. After 30 min, a
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mixture of (S)-H8-BINOL (7.4 mg, 0.025 mmol) and TiACHTUNTRGNE(UNG OiPr)4 (127 mL,
0.425 mmol) in THF (1 mL) was added. The solution was stirred for
30 min before 2-chlorobenzaldehyde (28.2 mL, 0.25 mmol) was added
dropwise. The reaction was stirred at room temperature and monitored
by TLC. After completion (3 h), the reaction mixture was quenched with
a saturated NH4Cl aqueous solution and extracted with ethyl acetate (3ꢂ
10 mL). The combined organic layers were washed with brine, dried over
Na2SO4, filtered, and the solvent was removed under reduced pressure.
The crude product was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate, 8:1) to give the pure product (51.4 mg,
94% yield, 94% ee).
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Acknowledgements
We are grateful to Prof. Dr. Patrick J. Walsh for his earnest and helpful
discussion on this work and the National Natural Science Foundation of
China for the financial support (No. 20672051).
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Keywords: aldehydes · arylation · asymmetric catalysis ·
asymmetric synthesis · Grignard reaction
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Received: April 15, 2010
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Published online: June 11, 2010
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